Spontaneous CNV in a Novel Mutant Mouse Is Associated With Early VEGF-A-Driven Angiogenesis and Late-Stage Focal Edema, Neural Cell Loss, and Dysfunction
Spontaneous CNV in a Novel Mutant Mouse Is Associated With Early VEGF-A-Driven Angiogenesis and Late-Stage Focal Edema, Neural Cell Loss, and Dysfunction
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DOI：
10.1167/iovs.14-13989
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发表时间：
2014-06-01
影响因子：
4.4
通讯作者：
Shima, David T.
中科院分区：
文献类型：
--
作者：
Nagai, Norihiro;von Leithner, Pete Lundh;Shima, David T.
目的.自发性脉络膜新生血管（sCNV）小鼠模型的特征及其对视网膜结构和功能的影响。sCNV小鼠表型的特征在于使用眼底照相术，荧光素血管造影术，共焦扫描激光检眼镜（SLO），光学相干断层扫描（OCT），ERG，免疫染色，生物化学，和电子显微镜。通过使用中和抗体研究了VEGF-A信号在sCNV中的作用，并通过细胞耗竭研究探索了巨噬细胞的作用。sCNV在出生后第10天至第15天（P10-P15）之间开始，数量和严重程度增加，导致RPE破坏和功能障碍。各种形态学方法证实了脉络膜起源和视网膜下的位置的血管生成血管。在大约P25时，视网膜外层存在血管，一些sCNV病变与视网膜血管吻合。通过全身阻断VEGF-A通路，CNV病变的数量显著减少。脉络膜新生血管的大小也通过减少病变相关巨噬细胞的数量来显著调节。sCNV的晚期与水肿、神经元丢失和功能障碍有关。sCNV小鼠是研究脉络膜新生血管相关的早期和晚期事件的新模型。用VEGF-A拮抗剂和抗炎策略在sCNV中的药理学减少表明该模型可用于研究用于治疗人类眼部新生血管性疾病的新靶点。
PURPOSE. Characterization of a mouse model of spontaneous choroidal neovascularization (sCNV) and its effect on retinal architecture and function.METHODS. The sCNV mouse phenotype was characterized by using fundus photography, fluorescein angiography, confocal scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), ERG, immunostaining, biochemistry, and electron microscopy. A role for VEGF-A signaling in sCNV was investigated by using neutralizing antibodies and a role for macrophages explored by cell-depletion studies.RESULTS. The sCNV starts between postnatal day 10 and 15 (P10-P15), increasing in number and severity causing RPE disruption and dysfunction. Various morphological methods confirmed the choroidal origin and subretinal position of the angiogenic vessels. At approximately P25, vessels were present in the outer retina with instances of anastomosis of some sCNV lesions with the retinal vasculature. The number of CNV lesions was significantly decreased by systemic blockade of the VEGF-A pathway. Choroidal neovascularization size also was significantly modulated by reducing the number of lesion-associated macrophages. Later stages of sCNV were associated with edema, neuronal loss, and dysfunction.CONCLUSIONS. The sCNV mouse is a new model for the study of both early and late events associated with choroidal neovascularization. Pharmacological reduction in sCNV with VEGF-A antagonists and an anti-inflammatory strategy suggests the model may be useful for investigating novel targets for treating human ocular neovascular disease.